This application focuses on myocardial ischemia, one of the main causes of heart disease. The objective of this proposal are to study a broad spectrum of the causes and consequences of myocardial ischemia, namely the mechanical, pharmacologic and biochemical factors that determine the maldistribution of coronary blood flow, with special reference to subendocardial ischemia; the metabolic and functional effects of such subendocardial ischemia with or without ventricular hypertrophy; the differences that may occur in myocardial blood flow and functional changes when hypertrophy occurs in infancy; the effects of myocardial ischemia on innervation of the heart and the predisposition to post- ischemic arrhythmias and, the effects of ischemia and hypoxia on adrenergic and cholinergic receptor on myocardial cell growth. The results of these studies dismutase genes in myocardial cells and their effect in reperfusion injury. The results of these studies should have wide applicability to patients with heart disease, ranging from methods of detecting early subendocardial ischemia before myocardial damage occurs to methods of preventing subendocardial ischemia after cardiac surgery, to understanding why ischemia causes dysfunction and how to ameliorate. To achieve the goals, Project 1 studies regional flows in whole hearts in animal models of normal and diseased hearts to find out how pressures, flows and heart rates interact to determine subendocardial flow, how phasic coronary flow patterns can be used to predict regional ischemia, how vasoactive peptides regulate coronary blood flow, and how hypercholesterolemia alters these coronary vascular responses. Project 2 examines the left ventricular response to stress, both with and without hypertrophy; isotopic and magnetic resonance spectroscopic studies of metabolism are made in these hearts. Project 4 uses radionuclide imaging of myocardial flow and norepinephrine uptake with metaiodobenzyl guanidine to determine how ischemia alters flow and nerve effectors, and uses electrophysiologic methods to assess the arrhythmic consequences of myocardial denervation. Project 3 examines the consequences of hypoxia and ischemia at the cellular level. It uses new and standard biochemical techniques to investigate what hypoxia does to myocardial cell receptors and second messengers, and molecular probes to study the effects of hypoxia on non myocardial cells.